E. Project Summary/Project 1 Metabolic disorders related to obesity (insulin resistance, type 2 diabetes, etc) have reached epidemic proportions in the United States due, in part, to a pervasive obesogenic environment. Increasingly, the public has turned to alternative medicine to provide resiliency to obesity-related metabolic dysfunction. However, the mechanism of action of many widely used botanicals is unknown and this lack of rigorous testing poses additional public health and safety concerns. This proposal focuses on the metabolic effects of Momordica charantia L. (bitter melon) and Artemisia dracunculus L., botanicals with a long history of use as dietary supplements. Our previous studies establish that an ethanolic extract of A. dracunculus, termed PMI 5011, in addition to bitter melon have cellular effects to improve insulin signaling and whole body effects to improve glucose metabolism. Thus, dietary intake of bitter melon or PMI 5011 abrogates many of the deleterious effects of obesity, an indication that these botanicals have great potential to promote resiliency to an obesogenic environment. Mechanistically, our findings are consistent with botanical regulation of the cellular ability to adapt to lipids as a fuel source in high-fat-induced obesity, suggesting a fundamental mechanism by which the botanicals improve metabolic resiliency to obesity is regulation of metabolic flexibility. We hypothesize that bitter melon and PMI 5011 promote metabolic resilience to metabolic dysfunction by regulating whole body substrate metabolism, skeletal muscle protein metabolism, and botanical-gene interactions in insulin responsive peripheral tissues as indicators of metabolic flexibility. In Aim 1, we will test the hypothesis that bitter melon and A. dracunculus promote resilience to an obesogenic environment by regulating the capacity to switch from carbohydrate to lipid oxidation in response to high fat diets (a measure of ?metabolic flexibility?). Aim 2 will test the hypothesis that maintenance of metabolic flexibility by bitter melon and A. dracunculus in an obesogenic environment is secondary to regulation of PGC-1 alpha-mediated gene expression across insulin responsive peripheral tissues. Aim 3 will test the hypothesis that maintenance of normal skeletal muscle structure and function via regulation of ubiquitin-proteasome protein degradation is a major contributing mechanism by which botanicals regulates metabolic flexibility in the presence of an obesogenic environment during aging. Together, these studies will comprehensively evaluate the mechanisms by which bitter melon and PMI 5011 improve resiliency to obesity-related metabolic dysfunction.by regulating metabolic flexibility.